This application claims priority to German Patent Application 10038709.8-44, filed Aug. 9, 2000, which is hereby incorporated by reference, in its entirety.
1. Field of the Invention
The present invention relates to substituted and unsubstituted 3H-benzo-[1,2,3]oxathiazole 2,2-dioxides, 1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxides and 1,3-dihydrobenzo[c]isothiazole 2,2-dioxides, to their preparation and to their use in medicaments.
2. Description of the Related Art
Aminobenzosultam derivatives acting as lipoxygenase inhibitors are known (WO 92/05164). Also known is the use of corresponding bifunctional derivatives as charge transporters in photoreceptors (JP 95/325942). Andersen et al. described the synthesis of toluenesulfonyl-protected derivatives and studies of reactions of these derivatives with nucleophiles (K. Andersen et al., J. Phys. Org. Chem., 10, 175-181 (1997); K. Andersen et al., J Org. Chem., 60, 2003-2007 (1995)).
It was an object of the present invention to provide novel substituted and unsubstituted benzooxathiazoles and their preparation and use as pharmaceutically active compounds. In particular, it was an object to provide novel substituted and unsubstituted benzooxathiazoles for treating type 1 and type 2 diabetes, insulin resistance and pathological obesity.
The present invention relates to compounds of the formula I 
in which
X is CH2, O, N;
Y is CH2, O, N;
R1, R2, R3 are each independently of one another
H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-,3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl; or in each case two of the radicals R1 and R2 or R2 and R3 or R1 and R3 together form a fused aryl radical, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2;
or its physiologically acceptable salts or prodrugs.
The invention preferably relates to compounds of the formula I wherein
X is O, N;
Y is O, N;
R1 is H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CONH(C1-C6)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
R2 is H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
R3 is H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl, NCO, NSO3-(C1-C10)alkyl;
or its physiologically acceptable salts or prodrugs.
The invention furthermore preferably relates to compounds of the formula I wherein
X is O, N;
Y is N;
R1 is H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
R2 is H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
R3 is COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl,
CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl, NCO, NSO3-(C1-C10)alkyl;
or its physiologically acceptable salts or prodrugs.
The invention furthermore preferably relates to compounds of the formula I wherein
X is O;
Y is N;
R1 is H, F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
R2 is F, Cl, Br, I, NH2, OH, NO2, COOH;
COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl, CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
(C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
R3 is COO(C1-C6)alkyl, CONH2, CONH(C1-C16)alkyl, CONH(C1-C16)alkenyl,
CONH(C1-C6)alkyl-phenyl, where phenyl may be mono- to trisubstituted by O-(C1-C10)alkyl or O-(C1-C10)alkyl-phenyl, CONH(C1-C6)alkyl-benzimidazole, where the benzimidazole ring may be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
O-(C1-C6)alkyl;
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl-COOH, (C1-C6)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl,
CONH2;
Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furanyl or 2-or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C10)alkyl, NH2, NH(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2; (C3-C18)cycloalkyl, where in the alkyl radicals one or more hydrogens may be replaced by fluorine or one hydrogen may be replaced by OH, (C1-C6)alkyl-phenyl or O-(C1-C6)alkyl-phenyl,
NCO, NSO3-(C1-C10)alkyl;
or its physiologically acceptable salts or prodrugs.
The invention further relates to a method of inhibiting a PTPase, preferentially PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or HePTP, comprising administering to a subject in need thereof an effective amount of one or more compounds of formula 1 as described above.
The invention further relates to a method of treating type 1 diabetes, type 2 diabetes, insuling resistance, or pathological obesity comprising administering to a subject in need thereof an effective amount of one or more compounds of formula 1 as described above.
The invention still further relates to a method of preparing a pharmaceutical composition comprising the steps of mixing one or more compounds of formula 1 with one or more pharmaceutically acceptable excipients and bringing this mixture into a form suitable for administration.
Other compounds, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
In a compound of the formula I, X and Y in preferred embodiments may in each case independently of one another be CH2, O or N.
The invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2 and R3 can be either straight-chain or branched.
On account of their higher water solubility, pharmaceutically acceptable salts are particularly suitable for medicinal applications compared with the starting materials or base compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and of organic acids, such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid. For medicinal purposes, the chlorine salt is particularly preferred. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).
Salts having a pharmaceutically acceptable anion are likewise included in the scope of the invention as useful intermediates for the production or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in-vitro, applications.
Salts of chemical compounds of the formula I can be prepared using customary methods familiar to the person skilled in the art. A salt can be prepared, for example, by combining a chemical compound of the formula I with an inorganic or organic acid or base in a solvent or diluent.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d used here relates to any physiologically acceptable derivative of a compound of the formula I according to the invention, for example an ester, which on administration to a mammal, such as, for example, man, is able (directly or indirectly) to form a compound of the formula I or an active metabolite thereof.
The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs can themselves be active or inactive.
The compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are included in the scope of the invention and are a further aspect of the invention.
Hereinbelow, all references to xe2x80x9ccompound(s) according to formula (I)xe2x80x9d refer to a compound/compounds of the formula (I) as described above, and to their salts, solvates and physiologically functional derivatives as described herein.
The amount of a compound according to formula (I) which is necessary in order to achieve the desired biological effect is dependent on a number of factors, for example the specific compound selected, the intended use, the manner of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes can contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individual doses can contain, for example, from 1 mg to 10 g of the active compound. Thus, ampoules for injections can contain, for example, from 1 mg to 100 mg, and orally administrable individual dose formulations, such as, for example, tablets or capsules, can contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight details relate to the weight of the dihydrothiazolium ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula (I) can be used themselves as the compound, but they are preferably present in the form of a pharmaceutical composition with a tolerable excipient. The excipient must of course be tolerable, in the sense that it is compatible with the other constituents of the composition and is not harmful to the patient""s health. The excipient can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds according to formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically acceptable excipients and/or auxiliaries.
Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable manner of administration in each individual case is dependent on the nature and severity of the condition to be treated and on the nature of the compound according to formula (I) used in each case. Sugar-coated formulations and sugar-coated delayed release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets which in each case contain a certain amount of the compound according to formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared by any suitable pharmaceutical method which includes a step in which the active compound and the excipient (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid excipient, after which the product is shaped, if necessary. Thus a tablet, for example, can be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be prepared by tableting the compound in free-flowing form, such as, for example, in a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent and/or one (a number of) surface-active/dispersing agent(s) in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound, moistened with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound according to formula (I) with a flavoring, customarily sucrose and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration preferably include sterile aqueous preparations of a compound according to formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration can also take place subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be prepared by mixing the compound with water and rendering the obtained solution sterile and isotonic with the blood. Injectable compositions according to the invention in general contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably present as individual dose suppositories. These can be prepared by mixing a compound according to formula (I) with one or more conventional solid excipients, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical application to the skin are preferably present as ointment, cream, lotion, paste, spray, aerosol or oil. Excipients which can be used are petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is in general present in a concentration of from 0.1 to 15%, for example of from 0.5 to 2%, by weight of the composition.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal administration can be present as individual patches which are suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active compound in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is from about 1% to 35%, preferably from about 3% to 15%. As a particular possibility, the active compound can be released by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6):318 (1986).
The invention furthermore relates to a process for preparing the compounds of the formula I, which comprises obtaining the compounds of the formula I in such a way that the procedure is according to the following reaction scheme:
A benzylidenediamine of the formula II in which R1, R2 and R3 are as defined in the sections above is reacted with sulfonediamine. In particular, it is possible to prepare a chemical compound of the formula I in which X is N and Y is N in this manner. 
It is also possible to prepare a compound of the present invention by reacting a 2-aminophenol of the formula III whose N group is protected and whose substituents R1, R2 and R3 are as defined under formula I with sulfuryl chloride, followed by removal of the protective group. The N group of the 2-aminophenol of the formula III is preferably protected by p-toluenesulfonyl.
Alternatively, a 2-aminophenol of the formula III in which the 2-aminophenol is present without protective group is used as starting material. This 2-aminophenol of the formula III whose N group is not protected and whose substituents R1, R2 and R3 are each defined as in claim 1 is treated with sulfonyldiimidazole under basic conditions. The base used can, for example, be triethylamine, a Hxc3xcnig base or DBU (1,5-diazabicyclo[4.3.0]non-5-ene). 
It is also possible to prepare a compound of the present invention by a process in which initially a 1-bromomethyl-2-nitrobenzene of the formula IV 
whose substituents R1, R2 and R3 are as defined under formula I with Na2SO3 (sodium sulfite) to give a compound of the formula V which is then converted by reduction of the nitro group into the corresponding aniline. A compound of the formula I is finally obtained by heating this aniline of the compound of the formula V.
The invention also relates to a pharmaceutical composition or medicament which comprises at least one of the compounds of the formula I and/or its physiologically acceptable salts and/or their prodrugs and, if appropriate, additional excipients.
The compounds of the formula I, and/or their physiologically acceptable salts and/or their prodrugs can be used for preparing medicaments.
Such medicaments are suitable, in particular, for treating type 1 and 2 diabetes, insulin resistance and pathological obesity. In addition, they are also suitable for treating elevated blood lipid levels, hypertension, atherosclerosis, immune system dysfunctions, autoimmune diseases, allergic diseases such as asthma, osteoporosis, disturbed proliferation, such as cancer and psoriasis, diseases where the production of growth factors, hormones or cytokines which effect the release of growth hormones is reduced or increased, infectious diseases or disorders of the nervous system, such as Alzheimer""s disease and schizophrenia.
The compounds of the formula I, and/or their physiologically acceptable salts and/or their prodrugs can furthermore be used for preparing a medicament which inhibits a PTPase. Suitable PTPases are, in particular, PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or HePTP.
Finally, compounds of the formula I and/or their physiologically acceptable salts and/or their prodrugs can be used for preparing a medicament for the treatment of diseases, in particular, type 1 and 2 diabetes, insulin resistance, pathological obesity, elevated blood lipid levels, hypertension, atherosclerosis, immune system dysfunctions, autoimmune diseases, allergic diseases such as asthma, osteoporosis, disturbed proliferation, such as cancer and psoriasis, diseases where the production of growth factors, hormones or cytokines which effect the release of growth hormones is reduced or increased, disorders of the nervous system such as Alzheimer""s disease and schizophrenia and infectious diseases.
The invention relates to the preparation of a medicament comprising at least one compound of this invention, which comprises mixing the active compound with a pharmaceutically acceptable excipient, and bringing this mixture into a form suitable for administration.
List of Abbreviations:
aa amino acids
DBU 1,5-diazabicyclo(4.3.0)non-5-ene
DMSO dimethyl sulfoxide
DTT dithiotreitol
EDTA ethylenediaminetetraacetic acid
EtOAc ethyl
EGTA ethylenebis(oxyethylenenitrilo)tetraacetic acid
h hour
HPLC high pressure liquid chromatography
MeOH methanol
MOI multiplicity of infection
MS mass spectroscopy
NMR nuclear magnetic resonance
PAGE polyacrylamide gel electrophoresis
RP reversed phase
RT room temperature
SDS sodium dodecylsulfate
TFA trifluoroacetic acid
The present invention, thus generally described, will be understood more readily by reference to the examples listed below, which serve to illustrate the present invention without limiting it.